New Findings on the Brain’s Immune Cells during Alzheimer’s Disease Progression

The plaque deposits in the brain of Alzheimer’s patients are surrounded by the brain’s own immune cells, the microglia. This was already recognized by Alois Alzheimer more than one hundred years ago. But until today it still remains unclear what role microglia play in Alzheimer’s disease. Do they help to break down the plaque deposit? A study by researchers of the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch and Charité – Universitätsmedizin Berlin has now shed light on these mysterious microglia during the progression of Alzheimer’s disease.

Dr. Grietje Krabbe of the laboratory of Professor Helmut Kettenmann (MDC) and Dr. Annett Halle of the Neuropathology Department of the Charité headed by Professor Frank Heppner demonstrated that the microglial cells around the deposits do not show the classical activation pattern in mouse models of Alzheimer´s disease. On the contrary, in the course of the Alzheimer’s disease they lose two of their biological functions. Both their ability to remove cell fragments or harmful structures and their directed process motility towards acute lesions are impaired. The impact of the latter loss-of-function needs further investigation. The plaques consist of protein fragments, the beta-amyloid peptides, which in Alzheimer’s disease are deposited in the brain over the course of years. They are believed to be involved in destroying the nerve cells of the affected patients, resulting in an incurable cognitive decline.

However, just why the microglial cells, which cluster around the deposits, are inactivated or lose their functionality is still not fully understood. The researchers concluded that this process occurs at a very early stage of disease development and is likely triggered by the beta-amyloid. This is confirmed by the fact that the loss-of-function of the microglial cells in the mice could be reversed by beta-amyloid antibodies thereby decreasing the beta-amyloid burden. According to the researchers, the potential to restore microglial function by directed manipulation should be pursued and exploited to develop treatments for Alzheimer’s disease.

'Strikingly similar' brains of man and fly may aid mental health research

A new study by scientists at King’s College London’s Institute of Psychiatry and the University of Arizona (UA) published in Science reveals the deep similarities in how the brain regulates behaviour in arthropods (such as flies and crabs) and vertebrates (such as fish, mice and humans).

The findings shed new light on the evolution of the brain and behaviour and may aid understanding of disease mechanisms underlying mental health problems.

Based on their own findings and available literature, Dr Frank Hirth (King’s) and Dr Nicholas Strausfeld (UA) compared the development and function of the central brain regions in arthropods (the ‘central complex’) and vertebrates (the ‘basal ganglia’).

Research suggests that both brain structures derive from embryonic stem cells at the base of the developing forebrain and that, despite the major differences between species, their respective constitutions and specifications derive from similar genetic programmes.

The authors describe that nerve cells in the central complex and the basal ganglia become inter-connected and communicate with each other in similar ways, facilitating the regulation of adaptive behaviours. In other words, the response of a fly or a mouse to internal stimuli such as hunger or sleep, and external stimuli such as light/dark or temperature, are regulated by similar neural mechanisms.

Dr Hirth from the Department of Neuroscience at King’s Institute of Psychiatry says: “Flies, crabs, mice, humans: all experience hunger, need sleep and have a preference for a comfortable temperature so we speculated there must be a similar mechanism regulating these behaviours. We were amazed to find just how deep the similarities go, despite the differences in size and appearance of these species and their brains.”

Dr Strausfeld, a Regents Professor in the UA’s Department of Neuroscience and the Director of the UA’s Center for Insect Science, says: “When you compare the two structures, you find that they are very similar in terms of how they’re organized. Their development is orchestrated by a whole suite of genes that are homologous between flies and mice, and the behavioral deficits resulting from disturbances in the two systems are remarkably similar as well.”

In humans, dysfunction of the basal ganglia can cause severe mental health problems ranging from autism, schizophrenia and psychosis, to neurodegeneration - as seen in Parkinson’s disease, motor neurone disease and dementia - as well as sleep disturbances, attention deficits and memory impairment. Similarly, when parts of the central complex are affected in fruit flies, they display similar impairments.

Dr Hirth (King’s) adds: “The deep similarities we see between how our brains and those of insects regulate behaviour suggest a common evolutionary origin. It means that prototype brain circuits, essential for behavioural choice, originated very early and have been maintained across animal species throughout evolutionary time. As surprising as it may seem, from insects’ dysfunctional brains, we can learn a great deal about how human brain disorders come about.”

The findings suggest that arthropod and vertebrate brain circuitries derive from a common ancestor already possessing a complex neural structure mediating the selection and maintenance of behavioural actions.

Although no fossil remains of the common ancestor exist, trace fossils, in the form of tracks criss-crossing the seafloor hundreds of millions of years ago, reveal purposeful changes in direction.

Dr Strausfeld (UA) says: “If you compare these tracks to the tracks left behind by a foraging fly larva on an agar plate or the tunnels made by a leaf-mining insect, they’re very similar. They all suggest that the animal chose to perform various different actions, and action selection is precisely what the central complex and the basal ganglia do.”

The trace fossils may thus support the early existence of brains complex enough to allow for action selection and a shared ancestry of neural structures between invertebrates and vertebrates.

Do drugs for bipolar disorder “normalize” brain gene function?

Every day, millions of people with bipolar disorder take medicines that help keep them from swinging into manic or depressed moods. But just how these drugs produce their effects is still a mystery.

Now, a new University of Michigan Medical School study of brain tissue helps reveal what might actually be happening. And further research using stem cells programmed to act like brain cells is already underway.

Using genetic analysis, the new study suggests that certain medications may help “normalize” the activity of a number of genes involved in communication between brain cells. It is published in the current issue of Bipolar Disorders.

The study involved brain tissue from deceased people with and without bipolar disorder, which the U-M team analyzed to see how often certain genes were activated, or expressed. Funding support came from the National Institutes of Health and the Heinz C. Prechter Bipolar Research Fund.

“We found there are hundreds of genes whose activity is adjusted in individuals taking medication – consistent with the fact that there are a number of genes that are potentially amiss in people with bipolar,” says senior author Melvin McInnis, M.D., the U-M psychiatrist, U-M Depression Center member and principal investigator of the Prechter Fund Projects who helped lead the study. “Taking the medications, specifically ones in a class called antipsychotics, seemed to normalize the gene expression pattern in these individuals so that it approached that of a person without bipolar.”

Digging deeper into bipolar genetics

Scientists already know that bipolar disorder’s roots lie in genetic differences in the brain — though they are still searching for the specific gene combinations involved.  

McInnis and his colleagues have now embarked on research developing several a lines of induced pluripotent stem cells derived (iPSC) from volunteers with and without bipolar disorder, which will allow even more in-depth study of the development and genetics of bipolar disorder.

The newly published study looked at the expression, or activity levels, of 2,191 different genes in the brains of 14 people with bipolar disorder, and 12 with no mental health conditions. The brains were all part of a privately funded nonprofit brain bank that collected and stored donated brains, and recorded what medications the individuals were taking at the time of death.

Seven of the brains were from people with bipolar disorder who had been taking one or more antipsychotics when they died. These drugs include clozapine, risperidone, and haloperidol, and are often used to treat bipolar disorder. Most of the 14 brain donors with bipolar disorder were also taking other medications, such as antidepressants, at the time of death.

When the researchers compared the gene activity patterns among the brains of bipolar disorder patients who had been exposed to antipsychotics with patterns among those who weren’t, they saw striking differences.

Then, when they compared the activity patterns of patients who had been taking antipsychotics with those of people without bipolar disorder, they found similar patterns.

The similarities were strongest in the expression of genes involved in the transmission of signals across synapses – the gaps between brain cells that allow cells to ‘talk’ to one another. There were also similarities in the organization of nodes of Ranvier – locations along nerve cells where signals can travel faster.

McInnis, who is the Thomas B. and Nancy Upjohn Woodworth Professor of Bipolar Disorder and Depression in the U-M Department of Psychiatry, worked with U-M scientists Haiming Chen, M.D. and K. Sue O’Shea, Ph.D., of the U-M Department of Cell and Developmental Biology. They also teamed with Johns Hopkins University researcher Christopher Ross, M.D., Ph.D. on the new research; U-M and Johns Hopkins have a long history of collaboration on bipolar disorder research.

The research used brain tissue samples from the Stanley Brain Collection of the Stanley Medical Research Institute in Maryland.

Using “gene chip” analysis to measure the presence of messenger RNA molecules that indicate gene activity, and sophisticated data analysis, they were able to map the expression patterns from the brains and break the results down by bipolar status and medication use. The bipolar and control (non-bipolar) brains were matched by age, gender and other factors.

“In bipolar disorder, it’s not just one gene that’s involved – it’s a whole symphony of them,” says McInnis, who has helped lead U-M’s bipolar genetics research for nearly a decade. “Medications appear to nudge them in a direction that aligns more with the normal expression pattern.”

Among those that were “nudged” were genes that have already been shown to be linked to bipolar disorder, including glycogen synthase kinase 3 beta (GSK3β), FK506 binding protein 5 (FKBP5), and Ankyrin 3 (ANK3).

Going forward, says McInnis, cell culture studies will be critical to studying how medications for bipolar disorder work, and to screen new molecules as potential new medications.

‘Revealing the scientific secrets of why people can’t stop after eating one potato chip

The scientific secrets underpinning that awful reality about potato chips — eat one and you’re apt to scarf ’em all down — began coming out of the bag today in research presented at the 245^th National Meeting & Exposition of the American Chemical Society, the world’s largest scientific society. The meeting, which news media have termed “The World Series of Science,” features almost 12,000 presentations on new discoveries and other topics. It continues here through today.

Tobias Hoch, Ph.D., who conducted the study, said the results shed light on the causes of a condition called “hedonic hyperphagia” that plagues hundreds of millions of people around the world.

“That’s the scientific term for ‘eating to excess for pleasure, rather than hunger,’” Hoch said. “It’s recreational over-eating that may occur in almost everyone at some time in life. And the chronic form is a key factor in the epidemic of overweight and obesity that here in the United States threatens health problems for two out of every three people.”

The team at FAU Erlangen-Nuremberg, in Erlangen, Germany, probed the condition with an ingenious study in which scientists allowed one group of laboratory rats to feast on potato chips. Another group got bland old rat chow. Scientists then used high-tech magnetic resonance imaging (MRI) devices to peer into the rats’ brains, seeking differences in activity between the rats-on-chips and the rats-on-chow.

With recent studies showing that two-thirds of Americans are obese or overweight, this kind of recreational over-eating continues to be a major problem, health care officials say.

Among the reasons why people are attracted to these foods, even on a full stomach, was suspected to be the high ratio of fats and carbohydrates, which send a pleasing message to the brain, according to the team. In the study, while rats also were fed the same mixture of fat and carbohydrates found in the chips, the animals’ brains reacted much more positively to the chips.

“The effect of potato chips on brain activity, as well as feeding behavior, can only partially be explained by its fat and carbohydrate content,” explained Tobias Hoch, Ph.D. “There must be something else in the chips that make them so desirable,” he said.

In the study, rats were offered one out of three test foods in addition to their standard chow pellets: powdered standard animal chow, a mixture of fat and carbs, or potato chips. They ate similar amounts of the chow as well as the chips and the mixture, but the rats more actively pursued the potato chips, which can be explained only partly by the high energy content of this snack, he said. And, in fact, they were most active in general after eating the snack food.

Although carbohydrates and fats also were a source of high energy, the rats pursued the chips most actively and the standard chow least actively. This was further evidence that some ingredient in the chips was sparking more interest in the rats than the carbs and fats mixture, Hoch said.

Hoch explained that the team mapped the rats’ brains using Manganese-Enhanced Magnetic Resonance Imaging (MEMRI) to monitor brain activity. They found that the reward and addiction centers in the brain recorded the most activity. But the food intake, sleep, activity and motion areas also were stimulated significantly differently by eating the potato chips.

“By contrast, significant differences in the brain activity comparing the standard chow and the fat carbohydrate group only appeared to a minor degree and matched only partly with the significant differences in the brain activities of the standard chow and potato chips group,” he added.

Since chips and other foods affect the reward center in the brain, an explanation of why some people do not like snacks is that “possibly, the extent to which the brain reward system is activated in different individuals can vary depending on individual taste preferences,” according to Hoch. “In some cases maybe the reward signal from the food is not strong enough to overrule the individual taste.” And some people may simply have more willpower than others in choosing not to eat large quantities of snacks, he suggested.

If scientists can pinpoint the molecular triggers in snacks that stimulate the reward center in the brain, it may be possible to develop drugs or nutrients to add to foods that will help block this attraction to snacks and sweets, he said. The next project for the team, he added, is to identify these triggers. He added that MRI studies with humans are on the research agenda for the group.

On the other hand, Hoch said there is no evidence at this time that there might be a way to add ingredients to healthful, albeit rather unpopular, foods like Brussels sprouts to affect the rewards center in the brain positively.

Sound stimulation during sleep can enhance memory

Slow oscillations in brain activity, which occur during so-called slow-wave sleep, are critical for retaining memories. Researchers reporting online April 11 in the Cell Press journal Neuron have found that playing sounds synchronized to the rhythm of the slow brain oscillations of people who are sleeping enhances these oscillations and boosts their memory. This demonstrates an easy and noninvasive way to influence human brain activity to improve sleep and enhance memory.

"The beauty lies in the simplicity to apply auditory stimulation at low intensities—an approach that is both practical and ethical, if compared for example with electrical stimulation—and therefore portrays a straightforward tool for clinical settings to enhance sleep rhythms," says coauthor Dr. Jan Born, of the University of Tübingen, in Germany.

Dr. Born and his colleagues conducted their tests on 11 individuals on different nights, during which they were exposed to sound stimulations or to sham stimulations. When the volunteers were exposed to stimulating sounds that were in sync with the brain’s slow oscillation rhythm, they were better able to remember word associations they had learned the evening before. Stimulation out of phase with the brain’s slow oscillation rhythm was ineffective.

"Importantly, the sound stimulation is effective only when the sounds occur in synchrony with the ongoing slow oscillation rhythm during deep sleep. We presented the acoustic stimuli whenever a slow oscillation "up state" was upcoming, and in this way we were able to strengthen the slow oscillation, showing higher amplitude and occurring for longer periods," explains Dr. Born.

The researchers suspect that this approach might also be used more generally to improve sleep. “Moreover, it might be even used to enhance other brain rhythms with obvious functional significance—like rhythms that occur during wakefulness and are involved in the regulation of attention,” says Dr. Born.

Why we buy music

New study shows what happens in the brain to make music rewarding

A new study reveals what happens in our brain when we decide to purchase a piece of music when we hear it for the first time. The study, conducted at the Montreal Neurological Institute and Hospital – The Neuro, McGill University and published in the journal Science on April 12, pinpoints the specific brain activity that makes new music rewarding and predicts the decision to purchase music.

Participants in the study listened to 60 previously unheard music excerpts while undergoing functional resonance imaging (fMRI) scanning, providing bids of how much they were willing to spend for each item in an auction paradigm. “When people listen to a piece of music they have never heard before, activity in one brain region can reliably and consistently predict whether they will like or buy it, this is the nucleus accumbens which is involved in forming expectations that may be rewarding,” says lead investigator Dr. Valorie Salimpoor, who conducted the research in Dr. Robert Zatorre’s lab at The Neuro and is now at Baycrest Health Sciences’ Rotman Research Institute. “What makes music so emotionally powerful is the creation of expectations. Activity in the nucleus accumbens is an indicator that expectations were met or surpassed, and in our study we found that the more activity we see in this brain area while people are listening to music, the more money they are willing to spend.”

The second important finding is that the nucleus accumbens doesn’t work alone, but interacts with the auditory cortex, an area of the brain that stores information about the sounds and music we have been exposed to. The more a given piece was rewarding, the greater the cross-talk between these regions. Similar interactions were also seen between the nucleus accumbens and other brain areas, involved in high-level sequencing, complex pattern recognition and areas involved in assigning emotional and reward value to stimuli.  

In other words, the brain assigns value to music through the interaction of ancient dopaminergic reward circuitry, involved in reinforcing behaviours that are absolutely necessary for our survival such as eating and sex, with some of the most evolved regions of the brain, involved in advanced cognitive processes that are unique to humans.

“This is interesting because music consists of a series of sounds that when considered alone have no inherent value, but when arranged together through patterns over time can act as a reward, says Dr. Robert Zatorre, researcher at The Neuro and co-director of the International Laboratory for Brain, Music and Sound Research. “The integrated activity of brain circuits involved in pattern recognition, prediction, and emotion allow us to experience music as an aesthetic or intellectual reward.”

“The brain activity in each participant was the same when they were listening to music that they ended up purchasing, although the pieces they chose to buy were all different,” adds Dr. Salimpoor. “These results help us to see why people like different music – each person has their own uniquely shaped auditory cortex, which is formed based on all the sounds and music heard throughout our lives. Also, the sound templates we store are likely to have previous emotional associations.”

An innovative aspect of this study is how closely it mimics real-life music-listening experiences.  Researchers used a similar interface and prices as iTunes. To replicate a real life scenario as much as possible and to assess reward value objectively, individuals could purchase music with their own money, as an indication that they wanted to hear it again. Since musical preferences are influenced by past associations, only novel music excerpts were selected (to minimize explicit predictions) using music recommendation software (such as Pandora, Last.fm) to reflect individual preferences.

The interactions between nucleus accumbens and the auditory cortex suggest that we create expectations of how musical sounds should unfold based on what is learned and stored in our auditory cortex, and our emotions result from the violation or fulfillment of these expectations. We are constantly making reward-related predictions to survive, and this study provides neurobiological evidence that we also make predictions when listening to an abstract stimulus, music, even if we have never heard the music before. Pattern recognition and prediction of an otherwise simple set of stimuli, when arranged together become so powerful as to make us happy or bring us to tears, as well as communicate and experience some of the most intense, complex emotions and thoughts.

(Image: Peter Finnie and Ben Beheshti)

Getting a grip on hand function: Discovering key spinal cord circuits

Professor and neurosurgeon Dr. Rob Brownstone and postdoctoral fellow Dr. Tuan Bui have identified the spinal cord circuit that controls the hands’ ability to grasp.

The world’s leading neuroscience journal, Neuron, published the breakthrough finding in its latest issue.

The researchers have found that a certain population of neurons in the spinal cord — called the dI3 interneurons — assess information from sensory neurons in the hands and then send the appropriate signals to motor neurons in the spinal cord, and hence to the muscles, to control the hands’ grip.

Importance of hand-grip control

“This circuit allows us to subtly and unconsciously adjust our grasp so we apply the right amount of force to whatever we’re holding,” says Dr. Brownstone, a professor in the Department of Medical Neurosciences and the Division of Neurosurgery. “This mechanism is disrupted in spinal cord injuries, which can completely eliminate the ability to grasp, and in neurodegenerative diseases like Alzheimer’s disease, which can lead to an uncontrollable reflexive grasp such that people grab and can’t let go of what they touch.”

Impaired hand function has a devastating effect on people’s independence and ability to function in daily life. As Dr. Brownstone points out, people with quadriplegia ranked hand function as their number-one priority, when asked in a 2004 survey which function they would most want to recover if they could. They rated hand function well above trunk stability, walking, sexual function, bladder and bowel control, and normal sensation.

An unexpected finding

Drs. Brownstone and Bui were testing a spinal cord circuit for its role in the rhythmic pattern of walking, when they found it controlled hand grip instead. “The mice with this circuit disrupted were walking just fine, but I found it was unusually easy to remove them from their cages,” recounts Dr. Bui. “Mice will usually grab onto the cage wires when you go take them out, so this really got us thinking.”

While Dr. Bui was pondering the meaning of this unexpected observation in the lab, Dr. Brownstone was in his neurosurgery clinic, assessing a patient who was unable to control her grasp. “When she took my hand, she was unable to let go,” he recalls. “I had to peel her fingers off one by one to release my hand.”

As they compared notes, Drs. Brownstone and Dr. Bui quickly realized they had come across the circuit that controls hand grasp. Struck by the implications of their observations, they embarked on a series of experiments — with collaborators, including Dr. Tom Jessell at Columbia University in New York City — which validated the finding.

A path to future treatments

Now that the researchers have identified the specific spinal cord circuit that controls hand grip, they can go on to find targets for potential treatments for impaired hand function. “It’s possible that a neurotransmitter or other agent could be delivered to the spinal cord to correct the faulty circuit,” notes Dr. Brownstone. “It could be a complex strategy, but understanding is always the first step.”

Dr. Brownstone is a Tier 1 Canada Research Chair in spinal cord circuits. His research is also supported through grants from the Canadian Institutes of Health Research. Dr. Bui is a key member of Dr. Brownstone’s research team in the Motor Control Lab at Dalhousie University, where they are identifying the neural circuits that control our ability to walk and move in coordinated ways. Their ultimate goal is to identify targets for therapies to restore lost motor function and control in people with spinal cord injuries and other neurological diseases.

Imaging Patients with Psychosis and a Mouse Model Establishes a Spreading Pattern of Hippocampal Dysfunction and Implicates Glutamate as a Driver

The hippocampus in schizophrenia is characterized by both hypermetabolism and reduced size. It remains unknown whether these abnormalities are mechanistically linked. Here we addressed this question by using MRI tools that can map hippocampal metabolism and structure in patients and mouse models. In at-risk patients, hypermetabolism was found to begin in CA1 and spread to the subiculum after psychosis onset. CA1 hypermetabolism at baseline predicted hippocampal atrophy, which occurred during progression to psychosis, most prominently in similar regions. Next, we used ketamine to model conditions of acute psychosis in mice. Acute ketamine reproduced a similar regional pattern of hypermetabolism, while repeated exposure shifted the hippocampus to a hypermetabolic basal state with concurrent atrophy and pathology in parvalbumin-expressing interneurons. Parallel in vivo experiments using the glutamate-reducing drug LY379268 and direct measurements of extracellular glutamate showed that glutamate drives both neuroimaging abnormalities. These findings show that hippocampal hypermetabolism leads to atrophy in psychotic disorder and suggest glutamate as a pathogenic driver.

Flies reveal that a sense of smell, like a melody, depends upon timing

The sense of smell remains a mystery in many respects. Fragrance companies, for instance, know it is crucial that chemical compounds in perfumes reach nostrils at different rates to create the desired sensory experience, but it is has been unclear why. Yale researchers decided to interrogate the common fruit fly for answers.

The team of Yale scientist Thierry Emonet, his postdoctoral associate Carlotta Martelli, and his colleague John Carlson systematically recorded both the stimulus reaching the fly and the responses of individual neurons over time. They found that the timing of neuronal response was independent of the concentration of the odor in the air, which in theory might help flies track fluctuating odor stimuli. However, the timing of neuronal response did depend on the identity of the odor.

Different odors elicited tiny delays in neural response. Such odor-dependent delays could be useful to the brain processing complex scents, say the scientists. The research also shows that specific interactions between odors and surfaces can affect the timing of the stimulus and therefore neural response.

Emonet says the findings suggest the world of smell is like music, in which chemical compounds of the scent act as notes and enable recognition of specific odors depending upon when they are played, or processed. For more information on the research, see the April 9 issue of the journal Neuroscience.